Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer

Jai Rautela, Nikola Baschuk, Clare Y Slaney, Krishnath M Jayatilleke, Kun Xiao, Bradley N Bidwell, Erin C Lucas, Edwin Hawkins, Peter Lock, Christina S F Wong, Weisan Chen, Robin L Anderson, Paul John Hertzog, Daniel Mark Andrews, Andreas Moller, Belinda S Parker

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47 Citations (Scopus)


Metastatic progression is the major cause of breast cancer related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1-/- mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1-/- mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host haematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating NK cell population. We find that in vivo stimulated NK cells derived from WT, but not Ifnar1-/- mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an anti-metastatic strategy.
Original languageEnglish
Pages (from-to)1207 - 1217
Number of pages11
JournalCancer Immunology Research
Issue number11
Publication statusPublished - 2015

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